{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:39:17Z","timestamp":1791376757638,"version":"4.3.2"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T00:00:00Z","timestamp":1627257600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>NAFLD prevalence has increased rapidly and become a major global health problem. Tumor necrosis factor \u03b1\u2013induced protein 8\u2013like 2 (TIPE2) plays a protective role in a cluster of liver diseases, such as autoimmune hepatitis, hepatitis B, and hepatocellular carcinoma. However, the function of TIPE2 in NAFLD remains unknown. Here, we investigated the role of TIPE2 in the development of NAFLD.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Our study found that <jats:italic toggle=\"yes\">in vitro<\/jats:italic> overexpression or knockout of TIPE2 significantly ameliorated or aggravated lipid accumulation and inflammation in hepatocytes exposed to metabolic stimulation, respectively. Consistently, <jats:italic toggle=\"yes\">in vivo<\/jats:italic> hepatic steatosis, insulin resistance, inflammation, and fibrosis were alleviated in hepatic <jats:italic toggle=\"yes\">Tipe2<\/jats:italic>\u2010transgenic mice but exaggerated in hepatic <jats:italic toggle=\"yes\">Tipe2<\/jats:italic>\u2010knockout mice treated by metabolic challenges. RNA sequencing revealed that TIPE2 was significantly associated with the mitogen\u2010activated protein kinase pathway. Mechanistic experiments demonstrated that TIPE2 bound with transforming growth factor beta\u2013activated kinase 1 (TAK1), prevented tumor necrosis factor receptor\u2013associated factor 6\u2013mediated TAK1 ubiquitination and subsequently inhibited the TAK1 phosphorylation and activation of TAK1\u2013c\u2010Jun N\u2010terminal kinase (JNK)\/p38 signaling. Further investigation showed that blocking the activity of TAK1 reversed the worsening of hepatic metabolic disorders and inflammation in hepatic\u2010specific <jats:italic toggle=\"yes\">Tipe2<\/jats:italic>\u2010knockout hepatocytes and mice treated with metabolic stimulation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>TIPE2 suppresses NAFLD advancement by blocking TAK1\u2010JNK\/p38 pathway and is a promising target molecule for NAFLD therapy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31832","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T03:50:40Z","timestamp":1616730640000},"page":"1300-1318","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":31,"title":["Tumor Necrosis Factor \u03b1\u2013Induced Protein 8\u2013Like 2 Alleviates Nonalcoholic Fatty Liver Disease Through Suppressing Transforming Growth Factor Beta\u2013Activated Kinase 1 Activation"],"prefix":"10.1097","volume":"74","author":[{"given":"Yupeng","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cardiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Graduate School of Peking Union Medical College,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cardiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Graduate School of Peking Union Medical College,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Cardiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Graduate School of Peking Union Medical College,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Cardiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Department of Cardiology,The First Hospital of Hebei Medical University,Hebei,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology,Renmin Hospital of Wuhan University,Wuhan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbin","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Cardiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Department of Cardiology,Zhengzhou University People's Hospital,Central China Fuwai Hospital,Central China Branch of the National Cardiovascular Center,Henan Provincial People's Hospital,Henan,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian\u2010Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems,State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifei","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering,College of Future Technology,Peking University,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Da","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiology,State Key Laboratory of Cardiovascular Disease,Fuwai Hospital,National Center for Cardiovascular Diseases,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Graduate School of Peking Union Medical College,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,China"},{"name":"Department of Cardiology and Institute of Vascular Medicine,Peking University Third Hospital,Key Laboratory of Molecular Cardiovascular Science,Ministry of 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